The normal cellular prion protein (PrP) is a highly conserved, widely expressed, glycophospholinositol (GPI)-anchored cell surface glycoprotein (Prusiner, S. B. (1998) Proc Natl Acad Sci. USA 95, 13363-13383; Brockes, J. P. (1999) Curr Opin Neurobiol. 9, 571-577). Since its discovery, most studies on PrP have focused on its role in a group of neurodegenerative conditions, known as prion diseases (Prusiner, S. B. (1998) Proc Natl Acad Sci. USA 95, 13363-13383; Brockes, J. P. (1999) Curr Opin Neurobiol. 9, 571-577). Little is known about PrP outside the nervous system.
The synthesis, processing and transit of PrP to the cell surface are complex and not completely understood (Hegde, R. S. et al., (2003) Trends Neurosci. 26, 337-339). Normally, PrP is present in lipid rafts and can function as a signaling molecule (Mouillet-Richard, S. et al., (2000) Science 289, 1925-1928; Taylor, D. R. et al., (2006) Mol Membr Biol. 23, 89-99). PrP has many binding partners, such as glycosyaminoglycans, copper, laminin receptor, N-CAM, heat shock proteins, dystroglycan, stress-inducible protein, selectin and glypican-1 (Caughey, B. et al., (1994) J. Virol. 68, 2135-2141; Brown, D. R. et al., (1997) Nature 390, 684-687; Rieger, R. et al., (1997) Nat Med. 3, 1383-1388; Schmitt-Ulms, G. et al., (2001) J Mol Biol. 314, 1209-1225; Edenhofer, F. et al., (1996) J. Virol. 70, 4724-4728; Keshet, G. I. et al., (2000) J Neurochem. 75, 1889-1897; Zanata, S. M. et al., (2002) Embo J. 21, 3307-3316; Li, C. et al., (2007) Biochem J.; Mani, K. et al., (2003) J Biol Chem. 278, 38956-38965). PrP also binds Grb2, an adapter protein, lipids and nucleic acids (Lysek, D. A., and Wuthrich, K. (2004) Biochemistry 43, 10393-10399; Mahfoud, R. et al., (2002) J Biol Chem. 277, 11292-11296; Gabus, C. et al., (2001) J Mol Biol. 307, 1011-1021). PrP plays a role in apoptosis in a cell context dependent manner (Chiarini, L. B. et al., (2002) Embo J. 21, 3317-3326; Paitel, E. et al., (2003) J Biol Chem. 278, 10061-10066; Kuwahara, C. et al., (1999) Nature 400, 225-226; Bounhar, Y. et al., (2001) J Biol Chem. 276, 39145-39149; Diarra-Mehrpour, M. et al., (2004) Cancer Res. 64, 719-727). A recent study found that normal PrP is involved in the proliferation of epithelial cells and in the distribution of junction associated proteins in human enterocytes in vitro and in intestine in vivo (Morel, E. et al., (2008) PLoS ONE 3, e3000). However, since the PrP deficient (Prnp−/−) mouse is viable and appears to be normal, the physiologic functions of PrP remain an enigma (Bueler, H. et al., (1992) Nature 356, 577-582; Westergard, L. et al., (2007) Biochem Biophys Acta. 1772, 629-644).
PrP is over-expressed in human gastric cancers (Liang, J. et al., (2006) Tumour Biol. 27, 84-91). Expression microarray study found that PRNP is also over-expressed in human colorectal cancers (Antonacopoulou, A. G. et al., (2008) Anticancer Res. 28, 1221-1227), and is one of the 25 genes that are over-expressed in pancreatic cancer cell lines (Han, H. et al., (2002) Cancer Res. 62, 2890-2896). However, the role PrP plays in tumorigenesis is not clear.
The most common human pancreatic cancer is ductal adenocarcinoma (PDAC), the fourth leading cause of cancer deaths in the U.S. (Jemal, A. et al., (2003) CA Cancer J Clin. 53, 5-26). The tumorigenesis of PADC is complex and not completely understood (Li, D. et al., (2004) Lancet 363, 1049-1057; Hezel, A. F. et al., (2006) Genes Dev. 20, 1218-1249). Evolution of human PDAC correlates with histological changes, characterized by the progression from a flat, columnar epithelium to a papillary, mucinous epithelium with increasing loss of cellular architecture and with nuclear atypia (Hruban, R. H. et al., (2001) Am J Surg Pathol. 25, 579-586; Hruban, R. H. et al., (2005) Methods Mol Med. 103, 1-13). These precursor lesions are commonly referred to as pancreatic intraepithelial neoplasia (PanIN-1, PanIN-2 and PanIN-3) (Hruban, R. H. et al., (2001) Am J Surg Pathol. 25, 579-586; Hruban, R. H. et al., (2005) Methods Mol Med. 103, 1-13).
Over the last decade, significant progress has been made in identifying molecular mechanisms underlying PDAC development (Deramaudt, T. et al., (2005) Biochim Biophys Acta. 1756, 97-101; Welsch, T. et al., (2007) Curr Mol Med. 7, 504-521; Maitra, A. et al., (2008) Annu Rev Pathol. 3, 157-188). The most common genetic lesions found in human PDAC are mutations in K-Ras, p53, DAPC-4 (Smad 4) and p16, suggesting that these genes are pivotal in the genesis of human PDAC. This interpretation is supported by studies in transgenic mouse models (Hingorani, S. R. et al., (2005) Cancer Cell 7, 469-483; Ijichi, H. et al., (2006) Genes Dev. 20, 3147-3160). It was found that mutation in K-Ras in association with additional genetic lesions, such as deletion of p53, p16 or Tgfbr 2 is sufficient to drive PDAC formation (Hingorani, S. R. et al., (2005) Cancer Cell 7, 469-483; Ijichi, H. et al., (2006) Genes Dev. 20, 3147-3160). However, other growth factor receptors, signal transducing molecules and cell surface molecules have also been implicated in PDAC carcinogenesis (Hezel, A. F. et al., (2006) Genes Dev. 20, 1218-1249; Maitra, A. et al., (2008) Annu Rev Pathol. 3, 157-188).